Advances in RNA modification in myocardial fibrosis (Review)

Myocardial fibrosis has emerged as a maladaptive remodeling process characterized by dysregulated extracellular matrix (ECM) deposition following cardiac injury. Recent studies have unveiled a complex RNA epitranscriptomic network that is composed of nine major types of RNA modification, namely N6‑methyladenosine (m6A), 1‑methyladenosine (m1A), 5‑methylcytosine (m5C), 7‑methylguanosine (m7G), N4‑acetylcytidine (ac4C), uridylation, adenosine‑to‑inosine (A‑to‑I) editing, pseudouridylation and U34 modification, which dynamically govern fibrotic pathogenesis by fine‑tuning RNA metabolism. Building on this knowledge, the present review proposed a three‑axis regulatory model to account for the underlying mechanism of RNA modification‑driven myocardial fibrosis. First, methylation‑acetylation synergy performs a pivotal role: Methyltransferase‑like (METTL) 3‑mediated m6A and N‑acetyltransferase 10‑driven ac4C modifications converge on the Hippo/Yes‑associated protein and TGF‑β/Smad signaling pathways, thereby exacerbating fibroblast activation and collagen overproduction. Secondly, single‑cell analyses have demonstrated the importance of cell‑type‑specific programming, where METTL1‑catalyzed m7G modifications selectively promote the differentiation of fibroblasts into profibrotic phenotypes, while sparing cardiomyocytes. Thirdly, cross‑modification crosstalk is handled by the RNA‑binding protein human‑antigen R, which integrates m6A, uridylation and A‑to‑I editing signals to regulate ECM dynamics, while the METTL3/fat mass and obesity‑associated protein balance modulates stress‑responsive RNA stability. In spite of these advances, however, the role of RNA modifications in myocardial fibrosis has yet to be fully elucidated. Critical gaps persist in our understanding of the spatial epitranscriptomic landscape, which necessitates the use of single‑cell technologies to map cell‑type‑specific modification patterns. Therapeutically, targeting nodal regulators, such as METTL1 inhibitors, holds promise for precision interventions. Additionally, combinatorial RNA modification signatures may serve as novel diagnostic biomarkers, although for this purpose, validation in clinical cohorts is required. Considered altogether, this framework repositions myocardial fibrosis as an RNA‑centric disorder, thereby challenging the traditional ECM‑centric position and offering fresh mechanistic insights into understanding myocardial fibrosis. Through integrating epitranscriptomic regulation into fibrotic signaling networks, new avenues are opened for therapeutic development in cardiac fibrotic diseases.